Study On The Correlation Between The Pharmacokinetics Of Nifedipine And Blood Pressure Changes In High Altitude Hypoxia

ObjectiveHypertension is the most common chronic disease,which can induce many complications and seriously threaten the life and health of patients.Nifedipine is the first-line medication for the treatment of hypertension,and it is also the basis of clini-cal combination medication.The plateau area of our country covers a large area and has the characteristics of low air pressure,low oxygen,low temperature,high altitude,high radiation,etc.,which leads to a series of changes in the body.The plateau low oxygen environment is one of the important factors affecting the pharmacokinetic parameters.Pharmacokinetic parameters are an important theoretical basis for guiding the dose and interval of clinical medication.At present,the basic research on the hum-an pharmacokinetic parameters of nifedipine in the plateau environment has not been reported.This makes the use of nifedipine in the plateau environment lack a certain human theory,and there is no relevant basis for the determination of the dose.There-fore,the purpose of this research is to investigate the effect of high altitude hypoxic environment on the pharmacokinetic parameters of nifedipine;whether changes in the pharmacokinetic parameters of nifedipine under high altitude hypoxic environment will affect its efficacy;it is nifedipine’s Pharmacokinetics and pharmacodynamics research provide reference,improve the safety of medication for people in plateau,and provide direction for the development of rational use of medication at plateau.MethodsExperimental research ethics plan for patients with hypertension:The research plan for the nifedipine trial was formulated,including:research objects,inclusion plan,design record report,trial research content,blood sample collection and processing.After the approval of scientific research ethics,relevant information and blood samples of patients in the plains and plateaus were collected.Establish a method for the determination of plasma concentration of nifedipine:Using UFLC-MS/MS analysis method,using acetonitrile solvent to precipitate the protein in plasma,nifedipine as the standard,nimodipine as the internal standard,and healthy plasma as the solvent,the concentration determination method was established and the method was verified.After complying with the"Guiding Principles for Validation of Biological Sample Quantitative Analysis Method"in the Chinese Pharmacopoeia,the concentration of nifedipine in plasma of patients with high blood pressure in the plains and plateaus was determined.Study on the pharmacokinetics of nifedipine under high altitude hypoxia:Based on the plasma concentration of nifedipine in patients on plateau and plains,the NONMEM method of population pharmacokinetics was used to establish a basic model and verify the basic model.Covariates（such as:weight,age,BMI,liver and kidney function,environment and other variables）,select the optimal population pharmacokinetic model,and verify the model,according to the final model to estimate the plain and plateau group nifedipine Pharmacokinetic parameters to investigate the effect of high altitude hypoxia environment on the kinetic parameters of nifedipine at the same dose.Evaluation of the antihypertensive efficacy of nifedipine under high altitude hypoxia:Taking blood pressure and heart rate as the main indicators of drug efficacy evaluation,according to my country’s guidelines and guidelines for clinical research on antihypertensive drugs:the recorded blood pressure and heart rate values of the plain and plateau groups are evaluated according to the standard level of efficacy:markedly effective,effective,and ineffective.The total effective rate of the plain and the plateau group was analyzed statistically to evaluate the effect of the plateau hypoxic environment on the antihypertensive effect of nifedipine.ResultsEstablish a method for determining the concentration of nifedipine in plasma:The linear equation of the method is:y=0.00297 x-0.00296,r²=0.9995,indicating that the method has a good linear relationship,and the accuracy is within9%.Above 90%,the RSD value of the recovery rate is less than 5%,and the RSD of the stability of the three schemes are all within 6%,indicating that the determination method is reliable,sensitive,accurate and stable.A total of 206 effective blood drug concentrations were determined,of which 106 were in 53 hypertensive patients in the plain group,and 100 were in 50 hypertensive patients at high altitude.Pharmacokinetics study of nifedipine under high altitude hypoxia:To establish a Pop PK model of nifedipine controlled-release tablets in patients with high altitude hypertension.Covariate environmental factors are the main reason for pharma-cokinetic parameters.Compared with the plain group,CL,K_e,T_1/2,AUC,and C_maxall changed significantly,among which CL and K_e increased by 34.84%and 28.57%,respectively,indicating that the excretion of nifedipine in patients under high altitude hypoxia environment Accelerated;T_1/2,AUC,C_max decreased by 16.40%,19.56%,17.81%,respectively.The bioavailability of nifedipine in patients with high altitude hypertension is low,and the metabolism is accelerated.The other pharmacokinetic parameters did not change significantly.Evaluation of the effect of nifedipine in lowering blood pressure under high altitude hypoxia:blood pressure:plain group:29 cases were markedly effective,11cases were effective,and 13 cases were ineffective,with a total effective rate of 75.47%;plateau group:13 cases were markedly effective,9 cases were effective,and28 cases were ineffective For example,the total effective rate is 44.00%.Heart rate:Plain group:28 cases were markedly effective,10 cases were effective,15 cases were ineffective,the total effective rate was 71.69%;the plateau group:10 cases were markedly effective,14 cases were effective,and 26 cases were ineffective,the total effective rate was 48.00%.Compared with the plain group,the total effective rate of blood pressure and heart rate indicators in the plateau group decreased by 31.47%and23.69%,respectively.There was a statistical difference,indicating that the use of the same dose of nifedipine as the plain did not effectively control blood pressure in the short term and was accompanied by heart rate.ConclusionThe pharmacokinetic parameters of nifedipine in humans under high altitude hypoxia environment change,and the changes in the parameters also lead to changes in the antihypertensive effect.In the pharmacokinetic parameters,the T_1/2 of the plateau group was significantly shortened,and the interval and dose of dosing could not be equal to the plain;the bioavailability was reduced,indicating that the concent-ration of the drug in the patient was reduced,and the target curative effect was not reached;from the pharmacodynamic index Considering ineffective treatment,not only fails to effectively control blood pressure and increases the damage of disease to organs,but also causes a waste of medical resources.Therefore,the research in this subject shows that the dosage of nifedipine at plateau cannot be used in the plain dosage.It is recommended to increase the dosage or the frequency of administration to increase the concentration of the drug in the body and achieve the goal of effective antihypertensive treatment..